A scar can be defined as an abnormal deposition of fibrous components, mostly matrix products such as collagen and fibronectin, at the site of injury. This deposition of fibrous tissue is in extreme abundance in comparison to normal skin. The result of this deposition is the granular surface or "lumpiness", which one would usually recognize as scar tissue. Besides its visual difference compared to normal skin, scar tissue also differs from normal skin in its bio-mechanical properties. Scar tissue, like other highly fibrous tissue, is less pliable and usually weaker in tensile strength. It is this loss of pliability and weakness which usually leads to the tissue's loss of function. For example, scarring of the hand, especially near joints, often leads to restricted movement, since the scarred skin can not stretch with the movement of the joint. Similarly, a scarred heart valve will be less strong and more prone to failure with a decrease in its tensile strength. (For a further discussion, see: Andrew's Diseases of the Skin, Domonkos, A. N., et al., W. B. Saunders Co., 1982, p. 18-19.)
The production of scar tissue as a sequelae of the healing of wounds or trauma is well known and many times thought to be an inevitable consequence of the healing process. In many cases, the scar tissue formed during the healing process is not a matter of great concern either medically or socially. However, there are abundant cases where the production of scar tissue is both of medical and social consequence to the individual. In cases when the initiating trauma to the patient involves areas of the body which are exposed to public view such as the face, arms or neck, scar formation can have lasting physiological and social implications to the patient. The physiological impact of a disfiguring facial scar due some traumatic event can in some people be devastating or at least discomforting depending on the severity of the disfigurement and the physiological makeup of the individual. In certain cases, a disfiguring scar can have not only a social stigma associated with it, but also an economic loss in those cases where personal appearances are an important attribute. Manytimes, it is often necessary or desirable to have reconstructive surgery to remove scar tissue for appearance sake. This necessity for surgery is a costly process in terms of economics as well as the pain and suffering which the patient must endure. It would be great benefit if there were a treatment available which would obviate the need for reconstructive surgery.
Additionally, there are cases where the formation of scar tissue from the healing process of a trauma has medical consequences apart from the potential unsightliness of scar formation. In these cases, the formation of scar tissue can inhibit the normal physiological function of a tissue to perform its normal role. Such an example would be the case of wide spread scarring such as that seen in severe burn cases. Patients who survived and have recovered from wide spread burns or who experienced burns in critical areas such as the hands or face, often have scar tissue which greatly decreases their ability regain normal movement and function of the affected areas. Such cases often require repeated surgery to allow the patient to regain function of the affected area and in many cases this reconstructive surgery is only partially effective, leaving the patient with some degree of permanent disability. Such a loss of tissue function can also be seen in cases where the trauma has been internal. The causes of internal trauma may originate from external sources such as puncture wounds or may be the inadvertent consequences of a beneficial surgical intervention such heart, vascular, neuro, or muscular operations. Regardless of cause, the formation of internal scar tissue can impair normal function. It would be of great medical benefit to have an agent which reduce the formation of scar tissue during the normal healing process.
Currently, there is no systemic agent which has shown to be efficatious in reducing the formation of scar tissue in humans. Surgical techniques and special wound dressings have been partially successful in reducing many cases of scar formation. However, these techniques may not be practical in cases where the damage is either wide-spread, such as burns, or impractical due to internal location.
Conditions which lead to scar formation as opposed to normal wound healing are poorly understood; however, there appears to be a link between the number, type, and duration of residence of inflammatory cells and the formation of scar tissue. Large influxes of inflammatory cells, especially macrophages, appear to promote the formation of scar tissue. Cytokines produced at the site of trauma have been implicated as factors in controlling the influx of inflammatory cells and hence, controlling the potential of scarring. In particulars a recent report in the literature by Shah et al., Lancet, 1992; 339: 213-214, implicates Transforming Growth Factor B (TGF-.beta.) as being a key cytokine which exacerbates scar formation a experimental, animal model of scarring.
TGF-.beta. is a peptide growth factor which refers to a generic family of peptides, often called isoforms meaning that members of the family either share amino acid homology and/or have similar physiological actions. Of particular interest to the subject of wound healing are: TGF-.beta.s 1, 2, and 3. For further discussion of the TGF-.beta. family of peptides, the subject is reviewed in Roberts A. B. and Sporn M. B., "The Transforming Growth Factor-.beta.s.", Sporn and Roberts, eds; "Peptide Growth Factors and Their Receptors I". Berlin, Springer Verlag, 1990 419-472. Additionally, TGF-.beta.s in wound healing, references in Ferguson, ibid., are germane.
Very recently, the literature reports that different isoforms of TGF-.beta. have different effects on scar formation. It has been demonstrated in experimental, animal scar models that TGF-.beta.1 appears to exacerbate the formation of scar tissue. However, it was shown that TGF-.beta.3 protected the skin from scar formation and allowed normal healing of the wound. The proposed mechanism for this action of TGF-.beta.3 was the decrease in macrophage and monocyte infiltration at the wound site. Ferguson, M. W., "Wound Healing, Scarring, TGF-.beta. antagonists and Isoforms," Abst. NIH TGF-.beta. Symposia, Bethesda Md., May 3, 1994.